This proposal describes a research plan and a 5-year mentored training program for the development of an academic career studying inherited retinal degenerations at the Casey Eye Institute at the Oregon Health & Science University (OHSU). The principal investigator, Mark Pennesi, MD/PhD, has a long-standing interest in studying retinal degeneration. As a newly appointed Assistant Professor at the Casey Eye Institute, he is pursuing a career path as a clinician scientist who sees patients with inherited retinal degenerations in the clinic, and also performs bench top research to understand these diseases and develop new therapies for them. As one of the premier NIH funded institutions, OHSU provides a unique environment for him to pursue basic science research, and also has the capacity to turn this research into clinical trials through its newly formed Translational Clinical Trials Center. The proposed career development plan will be composed of both research and clinical components. Richard Weleber, MD, Peter Francis, MD/PhD, and Rowland Taylor, PhD will all serve as mentors in different capacities. Dr. Weleber is a Professor at OHSU who will provide over thirty-five years of experience with inherited retinal degenerations as well as a vast knowledge of clinical electrophysiology. Dr. Francis is an Associate Professor at OHSU and is a clinician scientist with a strong clinical and basic science background in ophthalmic genetics. He has been involved in several translational projects including three clinical trials for retinal degenerations. Dr. Taylor is an Associate Professor at the Casey Eye Institute and has an extensive background in retinal electrophysiology and retinal immunohistochemistry. The focus of his research will be to develop new treatments for retinal degenerations such as Retinitis Pigmentosa (RP). RP is the most common causes of inherited blindness in the United States. There are currently no effective treatments to halt the visual deterioration in RP. Neurotrophic factors such as ciliary neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF) have been shown to prevent photoreceptor death in animal models of RP13-17, but such treatments require frequent injections or implanted drug release systems. An oral or topical medication that could up-regulate protective neurotrophic factors would result in a paradigm shift in the treatment for RP. One novel approach might be to increase the levels of neuroprotective growth factors, such as BDNF in the retina by administering oral selective serotonin reuptake inhibitors (SSRIs). SSRIs, such as fluoxetine or paroxetine, have been widely and safely used to treat a number of psychiatric diseases such as depression and anxiety. There is mounting evidence showing that the anti-depressive effects of SSRIs result from increased expression of BDNF in the brain18. Since SSRIs are already FDA approved drugs, positive findings from this study could rapidly translate to human clinical trials for currently incurable retinal diseases. The hypothesis of this proposal is that administration of SSRIs or serotonin receptor modulators (SRMs) will elevate levels of BDNF in the retina by facilitating its release from retinal pigment epithelium (RPE) cells thereby preventing retinal degeneration in rodent models of RP. The first specific aim will characterize the presence and distribution of serotonin receptors, serotonin transporters in the mouse and human retina and RPE. The second specific aim of this grant will determine whether SSRIs or other SRMs might have side effects on visual function by measuring the effects of these drugs on light responses in the rodent retina using electrophysiological techniques, such as the ERG and the multi-electrode array. The final specific aim of this grant will determine if serotonin receptor agonists, antagonists or SSRIs can modulate the levels of BDNF in cultured RPE. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore the potential of selective serotonin inhibitors and SRM to protect the retina in patients with retinal degenerative diseases that lead to blindness. While some of these diseases are rare, they can lead to complete blindness, thus making their impact on public health significant.